Substituted ethylamines



Patented Dec. 4, 1951 SUBSTITUTED ETHYLAMINES Louis H. Goodson, Kansas City, Mo., Robert Bruce Moflett and James E. Staflord, Kalamazoo, Mich., and Willard M. Hoehn, Kansas City, Mo., assignors to George A. Breon & Company, Kansas City, Mo., a corporation of Missouri No Drawing. Application November 19, 1948,

Serial No. 61,123 r '7 Claims. 1 This invention relates to certain 1,2-diarylethylamines and salts thereof which are valudialkyl, etc or can be a single divalent radical able as pharmaceutical agents and to the preparation thereof.

We have discovered that alpha-(tricyclic aryl) -beta- (monocyclic aryl) ethylamines, and salts thereof, are especially useful as pharmacological agents, for example for producing mild analgesia.

Our new amines have the genera1 formula Al'1-CH2'CH(A12)N:B, where Ari is 2, monocyclic aryl radical, such as phenyl, halophenyl, alkylphenyl, alkoxyphenyl, etc.; Arz is a tricyclic fused ring aryl radical, such as fiuorenyl, acenaphthyl, phenanthryl, anthryl, etc.; N:B is an amino group of the class consisting of the primary amino group -NH2, and aliphatic amino groups wherein the number of carbon atoms is 1-12, these groups including, for example, monoand dialkylamino, such as methylamino, ethylamino, isopropylamino, n-hexyh amino, dimethylamino, diethylamino', di-n-butylamino, etc.; alkenylamino, such as allylamino; monoand bis-(haloalkyl) amino, such as 2-bromoethylamino, 2-chloroethylamino, bis- (2-chloroethyl), etc.; monoand bis-(hydroxyalkyDamino, such as Z-hydroxyethylamino, (2- hydroxy-1-propyD'amino, bis(2-hydroxyethyl) amino, etc. aminoalkylamino, such as 2-diethyland such as alkylene or hetero-interrupted alkylene.

The compounds of our invention can be prepared by several synthetic methods. The method of choice in the preparation of a particular compound will vary according to availability or cost of the starting materials, yield of desired product, etc. In general, we have found it convenient to use one of the following processes.

(1) An aldehyde having the formula Ara-CHO is condensed with a primary amine having the formula I-IzN-B, where B represents an aliphatic radical wherein the number of carbon atoms is 1-12. The imine thus formed is treated with a Grignard reagent having the formula Ar1-Mg-halogen, and the Grignard addition product is hydrolyzed with mineral acid in con ventional manner, thus yielding the 1,2-diarylethylamine. These reactions can be represented by the following equations.

(c) (Addition product) For example:

1 C a a C Hr-ME-Cl HO] -CHCHz-CaH [Addition product] aminoethylamino, 2-dimethylaminoethylamino, 3-diethylaminopropylamino, 2-(2-hydroxyethy1- amino) ethylamino, 1-methyl-4- (diethylamino) butylamino, etc.; monoand di-cycloalkylamino, such as cyclopentylamino, cyclohexylamino, dicyclohexylamino, etc.; cyclic polymethyleneimino, such as l-piperidino, 2-methyl-1 piperidino, l-pyrrolidino, etc.; and cyclic polymethyleneimino interrupted by a hetero atom, such as 4-morpholino, N-piperazino, etc. The divalent grouping :B can thus be two separate monovalent radicals such as hydrogen and alkyl,

In the above process, when a 1,2-alkanolamine, such as ethanolamine, is employed to react with the aldehyde Ar2CHO, the resultin condensation product may be a 2-Arz-0XaZo1idine instead of the isomeric imine. However, the oxazolidine reacts in the subsequent Grignard reaction in the typical manner of the imines and thus the isomeric structure of the intermediate product is without consequence in the over-all process.

(2) A ketone having the formula is reacted with a salt of hydroxylamine, e. g. hydroxylamine hydrochloride, and the ketoxime thus formed is reduced to the corresponding amino compound. If desired, this primary amine in some instances can be alkylated to yield a secondary or tertiary amine derivative. These reactions can be represented by the following equations:

For example:

(11) HM... C

El Pt ('3) A halogen compound having the formula Ar1CH2-CH(halogen)-Ar2 is treated with ammonia, or a primary or secondary amine having the formula HN=B. The reaction proceeds according to the following equation:

Ar CHzOH(halogen)An'-i- HN=B As the primary or secondary amine, H-N=B, in this process there can be used, for example: monoand di-alkylamines such as m'ethyl'amine, diethylamine, dimethyl'ami'ne, n-butylamine, etc.; substituted alkylaznines, such asethanolamine, diethanolamine, dialkylamines, haloalkylamines, (4imorpholinoJ-alkylamines, etc.'-; and cyclic secondary amines of the polymethyleneimine type, such as morpholines, piperidines, pyrrolidines, etc. It will be understood that in using this process best results are obtained when secondary amines are employed, since in these instances a minimum of by-products will be formed in the condensatiom reaction.-

It is frequently preferable to isolate the final amine product obtainedv by the above processes as a salt such as the hydrochloride, from which, if desired, the free amine can be liberated by treatment with alkali.

The amines of our invention. are inmany cases Water-insoluble oils and it is often convenient-- to use them therapeutically as the more w'atersoluble acid addition salts, such as those derived from non-toxic inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and non-toxic organic acids, including tartaric acid, citric acid, succinic acid, and the like, can be employed. Our compounds can also be used in the form of quaternary ammonium salts derived from lower alkyl esters-of strong inorganic esters, organic sulfonic acids and the like, such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, methyl sulfate, etc.

Our invention is illustrated by the following examples Without, however, being limited thereto.

4 Example 1 N- 3-diethylaminopropyl) -alpha-' 5' acnaphthenyl) phenethylamine CHz-CFIz A A. 25' g. of 5-acenaphthenecarboxaldehyde in 250 ml. of benzene was mixed with 19.7 g. of

fi-om-O-oom. N-on N,N-diethyl-1,3-propanediamine and the mixture was allowed. to stand at room temperature for two days. From the reaction miktu-re there was obtained by distillation 17.1 g. of N-(B-diethylaminopropyl) 5.-' acenaphthenecarboxaldimine, boiling range 95-1'75 at 0.06 mm. pressure.

B. 16.1 g. of N-(diethylaminopropyl)5-acenaphthenecarboxaldimine'was treated with an ether solution of. benzylmagnesium chloride prepared by interaction of 27.7 g. of benzyl chlorideand 5.3 g. of magnesium and the mixture was'he'ated under reflux on a steam bath" for two' hours. The reaction mixture was then cooled and poured into a mixture. of ice and hydroc'hl'oric acid; The precipitate" which separated was collected on 'a filter, dried, and crystallized from: methanol' acet'one' mixture. There was thus obtained 20g; of crude? N; (3=diethylamino= propyl) alpha -(5 acenaphth'enylf-phenethyla mine dihydrochloride. The pure compound, obtainedby recrystallization from methanol, melted at 151-156" C. The free amine reacts with methyl iodide to form a methiodide.

Example 2 Alpha- (3-acenaphthenyl) phenethylamine A. A mixture-pf 10g. of 3-(pheny1acetyDacenaphthene, 10 gof hydro'xylamine hydrochloride, 507ml. of pyridineand 50 ml. of anhydrous ethanol washeated under reflux for three: hours. The solvents were evaporated from the mixture and the residue was washed with water and then dissolved in 50 ml. of ethanol. On cooling the alcoholic solution, 9 g. of B-(phenylacetyDacenaphthene oxime, M. P. 127-1-30 C., was obtained,

B. To a solution of 9 g. of 3-(phenylacetyD- acenaphthene oxime: in. ml. of ethanol there was added 7.2 g. of sodium. After the reaci tion had subsided, an addition 25 ml. of ethanol was added. After all of the sodium had reacted, 25 ml. of water was added, and the alcohol was evaporated from the mixture under reduced pressure. The residue Was extracted with ethyl ether. The ether solution, which contained ahaha-{fiacenaphthenyl)phenethylamine, was dried over anhydrous sodium sulfate, and hydrogen chloride was bubbled into the dry solution. There was thus precipitated 5.7 g. of alpha-(B-acenaphthenyDphenethylamine hydrochloride, M. P. 238-240 C.

Example 3 Alpha- (2-fiuorenyl) phenethylamine 19.5 g. of benzyl 2-fluorenyl ketoxime, prepared by interaction of benzyl Z-fluorenyl ketone and hydroxylamine hydrochloride, was reduced with sodium and ethanol in a manner similar to the reduction described in part B of Example 2. There was thus obtained 12 g. of alpha-(Z-fluorenyDphenethylamine hydrochloride, M. P. 255- 265 C.

Example 4 Alpha- (fi-acenaphthenyl) phenethylamine A. A mixture of g. of 5-(phenylacetyl)acenaphthene, 10 g. of hydroxylamine hydrochloride and 50 ml. of ethanol was heated on a steam bath for two hours and then the solvents were evaporated from the reaction mixture at reduced pressure. The residue was washed with water and crystallized from ethanol. There was thus obtained 7 g. of 3-(phenylacetyl)acenaphthene oxime, M. P. 134-136 C.

B. To a solution of '7 g. of 5-(phenylacety1)- acenaphthene oxime in '70 ml. of boiling ethanol there was added 7 g. of sodium. After the reaction had subsided, an addition ml. of ethanol was added to the reaction mixture. After all of the sodium had reacted, 25 ml. of water was added, and the alcohol was evaporated from the mixture under reduced pressure. The residue was stirred with water and ether. The ether layer, which contained alpha-(5-acenaphthenyl) phenethylamine, was separated, dried, and hydrogen chloride was bubbled into the ether solution. The solid which precipitated was alpha- (5-acenaphthenyl) phenethylamine hydrochloride, M. P. 221 C. (dec.).

We claim:

1. A compound of the group consisting of l-(tricyclic aryl) -2(monocarbocyclic aryl) ethylamines having the formula AnCHrCH-Arz where Ari is a member of the class consisting of phenyl and methoxyphenyl radicals; Ari is a tricyclic fused-ring carbocyclic aryl hydrocarbon radical of the class consisting of fluorenyl. acenaphthenyl, and anthryl radicals; and N=B is an amino radical of the class consisting of the primary amino group NHz, the methylamino radical, and [(di-lower alkyl)amino-lower alkyl]-NH- radicals wherein the number of carbon atoms does not exceed 12; and addition salts thereof.

2. An addition salt of a compound having the formula Ar OHgCHAr2 where Ari is phenyl; Al'z is an acenaphthenyl radical; and N=B is the primary amino group NH2.

3. An addition salt of a compound having the formula AnCHzCH-Arz where Ari i phenyl; Arz is a fluorenyl radical; and N=B is the primary amino group NH2.

4. An addition salt of alpha-(S-acenaphthenyDphenethylamine, said amine having the formula 5. An addition salt of alpha-(2-fiuorenyD- phenethylamine, said amine having the formula 6. An addition salt of alpha-(5-acenaphthenyDphenethylamine, said amine having the formula CH -CH:

7. An addition salt of N-(3-diethylaminopropyl) alpha- (5 acenaphthenyl) phenethylamine, said amine having the formula LOUIS H. GOODSON'. ROBERT BRUCE MOFFETT. JAMES E. STAFFORD. WILLARD M. HOEHN.

REFERENCES CITED The following references are of record in the file of this patent:

Gonzales, Bull. soc. chim., vol. 37, pp. 1591- 1596 (1925). 

1. A COMPOUND OF THE GROUP CONSISTING OF 1-(TRICYCLIC ARYL)-2-(MONOCARBOCYCLIC ARYL)ETHYLAMINES HAVING THE FORMULA 